The only proven way to reduce cancer risk in smokers is complete cessation, but many smokers are unable or unwilling to quit. Conceptually, if individuals could reduce their exposure to tobacco smoke toxicants, then their risk of disease could be lessened. This concept is known as harm reduction, and could be achieved through the aid of new strategies and tobacco products that provide an alternate source of nicotine. These are called potential reduced exposure products (PREPs)). There are PREPs that are cigarette-like, but also nicotine replacement therapy and smokeless tobacco are also considered to be PREPs. In the past, various experimental models have been used to evaluate tobacco-associated cancer risk, but none of these models are considered to produce sufficient results by themselves, better screening methods are needed, and currently a panel of models is used in combination. PREPs can be tested similarly, but to date, this has not been evaluated. Because PREPs will be used by individuals with widely differing prior tobacco use histories, the testing paradigms call for a assessing risks with reduced exposures following a background of carcinogen exposure (e.g., a "reversed dose-response relationship"). Whether this can be done successfully also has not been evaluated. This proposal will make use of a panel of conventional and novel testing paradigms that will, and importantly we will incorporate exposures using cigarette smoke condensates that simulate "human like" puffing profiles, and assess the effects of varying nicotine exposure. The goals of this proposal are 1) to develop the tools necessary to provide the objective scientific evidence required to adequately evaluate the ability of PREPs to reduce harm in the laboratory setting, and 2) to use these tools to evaluate existing PREPs and new products as they come to market. Both in vitro and in vivo models will be used in a stepped approach, and both conventional (SENCAR mice) and genetically engineered mice will be tested. The animal models will use skin painting exposures, but DNA adducts in lung tissues also will be assessed. The overall purpose of these experiments is to determine the feasibility of testing different types PREPs using experimental models. The importance of this issue is highlighted by the Program Announcement for PREP studies, and this proposal is responsive to that.